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Objectives

The following module was designed to supplement the clinical experience of medical students. It covers the anatomy, epidemiology, screening, presentation, diagnosis, staging, prognosis, treatment, and follow up care of esophageal cancer.

By the end of the module, the following objectives should be addressed:

  1. Review the gross anatomy of the esophagus and its surrounding structures. 
  2. Describe the layers of the esophageal wall and their importance in staging esophageal cancer.
  3. Recognize the two major histologies of esophageal cancer
  4. Know the risk factors corresponding to each of the two major histologies.
  5. Estimate the incidence of esophageal cancer.
  6. Understand the role of screening for esophageal cancer in asymptomatic adults. Identify which patient populations should be screened.
  7. Recognize that dysphagia and weight loss are the most common presenting symptoms of esophageal cancer. 
  8. Know the indications for further workup, including unexplained dysphagia and weight loss.
  9. Describe the components of a workup for suspected esophageal cancer.
  10. List factors affecting the prognosis and treatment of esophageal cancer.
  11. Understand that patients treated with curative intent are nonetheless at risk for recurrence and that this risk is mostly front-loaded. 
  12. Understand that surgery, chemotherapy, and radiation therapy all have roles in the treatment of esophageal cancer. Appreciate that most patients with esophageal cancer will benefit from multidisciplinary input (e.g. consultations, tumor boards).
  13. Describe common and serious complications that can arise during and after the treatment of esophageal cancer.
  14. List components of routine follow up of esophageal cancer post-treatment.
  15. Know that distal failure is more common than local failure for patients who were treated with curative intent.

Anatomy

The esophagus is a 25cm-long tube-like organ serving as a conduit between the pharynx and the stomach. It is bordered superiorly by the hypopharynx at the level of the C6 vertebra. Anteriorly, this corresponds to the inferior margin of the cricoid cartilage. The esophagus passes through the mediastinum and enters the abdomen at the esophageal hiatus of the diaphragm. Beyond, the esophagus continues briefly before terminating at the esophagogastric junction (EGJ). The esophagus can be divided into three segments -- cervical, thoracic, and abdominal:

  1. The cervical esophagus runs posterior to the trachea for 4-5cm before ending at the level of the thoracic inlet. This segment borders the carotid sheath, recurrent laryngeal nerve, and thyroid gland bilaterally as well as the thoracic duct to the left. Posteriorly, the cervical esophagus rests on the vertebral column.
  2. The thoracic esophagus spans from the thoracic inlet to the EGJ at the level of T11. This segment is subdivided into the upper thoracic, midthoracic, and lower thoracic regions. The border between the upper thoracic and midthoracic esophagus is at the level of the tracheal bifurcation.The midthoracic esophagus continues to the level of the inferior pulmonary veins, where it becomes the lower thoracic esophagus. As it descends, the thoracic esophagus passes posteriorly to the aortic arch, arch of the azygos vein, right pulmonary artery, left atrium, and left main bronchus before entering the abdomen through the esophageal hiatus.
  3. The abdominal esophagus is a short segment of the esophagus below the esophageal hiatus which overlaps with the lower thoracic esophagus. Some authors include 2cm of the gastric cardia, beyond the EGJ, in the definition of the abdominal esophagus. The abdominal esophagus is primarily retroperitoneal, although a small portion is covered by peritoneum/serosa. Inside the abdomen, the esophagus passes behind the left lobe of the liver.

The wall of the esophagus is divided into four main layers. From inside to outside, these are:

  1. Mucosa which consists of stratified squamous epithelium, lamina propria, and muscularis mucosa. The squamocolumnar junction or Z-line separates the stratified squamous epithelium of the esophagus and simple columnar epithelium of the stomach. Ordinarily, the Z-line coincides with the EGJ. However, in Barrett’s esophagus, metaplasia causes the squamocolumnar junction to migrate proximally.
  2. Submucosa
  3. Muscularis propria. The upper third of the esophagus is striated muscle while the lower third is smooth muscle. A mixture of both striated and smooth muscle can be found in the middle third of the esophagus.
  4. Adventitia, with a small amount of peritoneal (serosal) covering of the abdominal esophagus. The esophagus’s thin adventitia and lack of serosa facilitate the locoregional progression of esophageal cancer.

Classification

Esophageal squamous cell carcinoma (ESCC) accounts for nearly 90% of esophageal cancers worldwide, but only 31% of new cases in the US [1, 2]. Esophageal adenocarcinoma (EAC), a relative rarity worldwide, is responsible for 64% of new diagnoses in the US [2]. The predominance of adenocarcinoma is also observed in other high-income Western countries [1]. Much rarer cancers involving the esophagus include adenocystic, mucoepidermoid, small cell, and sarcomatoid carcinomas as well as lymphoma, Kaposi sarcoma, and melanoma; individually, these account for less than 1% of esophageal cancers [3].

Tumor location is important in the discussion of esophageal cancer as it affects staging and treatment. The prevalent histology also differs depending on location. Whereas EAC usually arises from the lower third of the esophagus, ESCC shows a predilection for the middle third. Esophageal cancer involving the upper third of the esophagus is rare but predominantly ESCC [4].

Adenocarcinoma near the cardia are further grouped by the Siewert classification [5]:

  1. Type I: tumor epicenter located 1-5cm above the EGJ
  2. Type II: tumor epicenter located 1cm above to 2cm below the EGJ. These are the true tumors of the cardia.
  3. Type III: tumor epicenter located 2-5cm below the EGJ.

Siewert type I and II adenocarcinomas are staged as esophageal cancer while Siewert type III adenocarcinomas are staged as gastric cancer [6].

Epidemiology

Esophageal cancer is uncommon in the West. In Canada, there were 2300 new diagnoses of esophageal cancer in 2017. It was responsible for 2200 deaths owing to the advanced stage at which most are diagnosed [7]. Globally, there were 572,000 new diagnoses and 509,000 deaths in 2018. Esophageal cancer is more prevalent worldwide, ranking 9th in incidence and 6th in mortality among cancers [8].

There is a trend toward higher incidence rates of EAC and lower incidence rates of ESCC in high-income Western countries, including Canada and the United States [2, 9, 10]. EAC has overtaken ESCC as the most common histology of esophageal cancer in many Western countries despite the global prevalence of ESCC [2, 9]. This divergent trend has been attributed to increasing rates of obesity and GERD, which are strongly associated with EAC, and decreasing rates of smoking, a leading cause of ESCC [9, 11].

Risk factors

Tobacco smoking

There are strong dose and duration-response relationships between smoking and the risk of developing ESCC or EAC [12-14]. Moreover, tobacco and alcohol consumption appears to have a synergistic effect on the risk of ESCC [15]. After smoking cessation, risk of esophageal cancer decreases over time, although ex-smokers remain at elevated risk compared to lifelong nonsmokers [13, 14].

Alcohol

Heavy alcohol consumption has been found to increase the risk of developing ESCC but not EAC [16, 17]. Alcohol consumption and tobacco smoking synergistically increase the risk of ESCC [15]. 

Obesity

Overweight and obese patients are at increased risk of developing EAC, possibly as a result of increased GERD [18]. In contrast, elevated BMI appears to have a protective effect in ESCC [19, 20]. 

GERD

Patients experiencing symptoms of gastroesophageal reflux are at a markedly higher risk of developing EAC. Having prolonged, more frequent, or more severe reflux symptoms confers additional risk [21].

Barrett’s esophagus

Barrett’s esophagus, with estimated prevalences of 1-7% in the general population and 5-15% in patients with GERD, is believed to be a precursor to most cases of EAC [22-25]. Patients with Barrett’s esophagus are estimated to have a 0.5% annual risk of developing EAC [26].

Diet

It appears that diets rich in meat, particularly red meat, increase the risk of EAC. On the other hand, consumption of fruits and vegetables may have a protective role in EAC [27]. There is epidemiologic evidence that nutritional deficiencies in riboflavin, nicotinic acid, magnesium, and zinc account for some of the increased risk of ESCC observed in high-risk regions [28, 29].

Achalasia

Achalasia dramatically increases the risk of ESCC and, to a lesser extent, EAC [30-32]. It is worth noting that obstruction by lower esophageal cancer can resemble achalasia, leading to misdiagnosis. As a result, the risk of esophageal cancer is especially high in the first year following the diagnosis of achalasia [33]. 

Sex

Adjusted for age, men are around fourfold more likely to develop esophageal cancer [2, 34]. Men are projected to account for 1800 of the 2300 annual cases of esophageal cancer in Canada [7].

Age

The incidence rate of esophageal cancer increases with age. Among those newly diagnosed with esophageal cancer in the US, 98% are at least 45 years old [2].

Race and Ethnicity

Geographically, the incidence of esophageal cancer is highest in East Asia, followed by Southern Africa, Eastern Africa, and Northern Europe [8]. The incidence in many of these regions reaches ten to twenty-fold that of the US [30]. While most esophageal cancers diagnosed in these high-incidence regions are ESCC, their etiology is less clear than those diagnosed in the West [8]. Possible culprits include HPV infection and dietary deficiencies, but a causal link has not been established [28, 29, 33].

In the US, Caucasians have higher incidence rates of esophageal cancer than Asians, Hispanics, American Indians, and Blacks. Caucasians are at particular risk for EAC, while Blacks and Asians more commonly develop ESCC [2].

Family history and genetics

Studies completed in endemic areas have consistently found positive family history to increase the risk of ESCC. However, aside from one Swedish study on EAC, studies in the West have failed to replicate this association [35-37].

Hereditary conditions linked to ESCC include Plummer-Vinson syndrome, Faconi anemia, Bloom syndrome, and tylosis [3]. Those with an extensive family history of Barrett’s esophagus or EAC are recognized as having familial Barrett’s esophagus and carry an increased risk of developing EAC [38]. These hereditary syndromes account for a small minority of esophageal cancers.

Summary of risk factors

A summary of risk factors for ESCC and EAC is below. Esophageal cancer is relatively rare, so the risk of developing esophageal cancer in most patients with these risk factors remains low. The next section will cover the major risk factors that warrant screening.


Table 1 Risk factors of esophageal cancer

Screening

As esophageal cancer is uncommon in the general population, no major Western organization endorses the screening of average-risk asymptomatic adults. However, there is considerable value in early detection, as the disease is usually minimally symptomatic until an advanced stage is reached, at which time prognosis is dismal. Screening should therefore be targeted those patients who are at highest risk for esophageal cancer.

As the risk factor most heavily implicated in the rise of EAC in Western countries, screening patients with reflux has attracted the attention of multiple professional organizations including the American College of Physicians, the American College of Gastroenterology, and the American Society of Gastrointestinal Endoscopy [46-48]. The Canadian Task Force on Preventive Health is anticipated to release its own guidelines on the subject in 2019. Guidelines published to date are mostly consistent. They all agree that upper endoscopy is indicated in patients presenting with GERD and concomitant warning symptoms described in the next section. The ACP and ASGE further recommend investigating reflux symptoms that are refractory to treatment. Endoscopy may also be appropriate in patients with longstanding or severe reflux symptoms and multiple additional risk factors, including:

  1. Male sex
  2. Age >50
  3. Caucasian race
  4. Elevated BMI
  5. Known hiatal hernia
  6. History of tobacco smoking
  7. Nocturnal reflux symptoms
  8. Positive first-degree family history of EAC or Barrett’s esophagus.

Patients who do not have any evidence of EAC or Barrett’s esophagus on screening endoscopy do not need repeat endoscopy. On the other hand, patients found to have Barrett’s esophagus should consider endoscopic surveillance and treatment of dysplasia. 

Severe caustic injury is strongly associated with ESCC, allegedly increasing risk by a thousandfold. There is, on average, a 40-year latency between the time of injury and the development of esophageal cancer. The ASGE recommends beginning endoscopic surveillance 15-20 years after injury [49].

Patients with achalasia also have a high (1 in 300 patient-years) risk of developing esophageal cancer. However, the number of endoscopies needed for each early diagnosis (400) and poor prognosis in this patient group has led the ACG and ASGE to withhold their endorsement [49, 50]. Practice in the field varies [51].

Finally, the merits of screening patients with hereditary cancer syndromes are considered case by case owing to their heterogeneity. The NCCN provides screening recommendations for some genetic conditions implicated in esophageal cancer [38].

Presentation and Diagnosis

Early esophageal cancer is usually asymptomatic. The most common symptoms at the time of diagnosis are dysphagia and weight loss, present in 74% and 57% of patients respectively. Other rarer (present in <20%) symptoms include odynophagia, symptoms of reflux refractory to treatment, recurrent vomiting, evidence of upper GI bleed, dyspnea, hoarseness due to recurrent laryngeal nerve involvement, and cervical lymphadenopathy [52]. Physical examination is usually normal in patients with esophageal cancer, and positive findings such as a palpable mass, lymphadenopathy, organomegaly, or cardiorespiratory abnormalities imply very advanced disease. A summary of features to consider on history and physical is provided below.


Table 2 Assessment of suspected esophageal cancer

In the absence of an alternative explanation, patients experiencing any of the warning symptoms described in Table 2 require further investigation [53, 54]. Upper endoscopic examination with biopsy is the diagnostic test of choice for esophageal cancer. In addition to cancer, upper endoscopy is also valuable in ruling out many other causes of these warning symptoms. The value of routinely adding barium swallow to endoscopy, as is traditional, is unclear; however, barium swallow is compulsory if there is a suspicion for tracheoesophageal fistula [54].

Investigations

Once the diagnosis of esophageal cancer is established, the following tests can be considered for staging and to guide treatment:

  1. CBC and CMP
  2. Endoscopic ultrasound with fine needle aspiration of suspicious nodes unless metastatic or unresectable
  3. Endoscopic resection of cT1a and small (up to 2cm) cT1b tumors
  4. Bronchoscopy if tumor located at or above the level of the carina
  5. Consider laparoscopic staging and peritoneal washings for cT3, node-positive, or Siewert type II and III tumors.
  6. CT chest, abdomen with oral and IV contrast. CT pelvis if clinically indicated.
  7. PET/CT skull base to mid-thigh if no evidence of metastatic disease
  8. MSI-H/dMMR and PD-L1 status if M1 disease is suspected, also add HER2 for M1 adenocarcinoma

Staging and Grading

AJCC 8th edition (2017) T staging

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis:
high-grade or dysplasia
T1a:
tumor invades lamina propria or muscularis mucosa
T1b:
tumor invades submucosa
T2:
tumor invades muscularis propria
T3a:
tumor penetrates adventitia
T4a:
tumor invades pleura, pericardium, azygos vein, or peritoneum
T4b:
tumor invades other adjacent structures such as the aorta, an airway, or a vertebral body

AJCC 8th edition (2017) N staging

NX: lymph nodes cannot be assessed
N0:
no regional lymph node metastases
N1:
1-2 positive regional lymph nodes
N2:
3-6 positive regional lymph nodes
N3:
7 or more positive regional lymph nodes

*regional lymph nodes refer to lower cervical paratracheal; upper and lower paratracheal; subcarinal; upper, middle, and lower thoracic esophageal; pulmonary ligament; diaphragmatic, paradarcial; left gastric; common hepatic; splenic; celiac; and cervical periesophageal H&N level VI and VII nodes

AJCC 8th edition (2017) M staging

M0: no distant metastases
M1:
distant metastases are present

Histologic grade

GX: grade not available
G1:
well differentiated
G2:
moderately differentiated
G3:
poorly differentiated

AJCC 8th edition (2017) prognostic stage groups

The prognostic grouping of esophageal cancers depend on histology.

ESCC prognostic stage groups

Whether the tumor is located in the upper (cervical and upper thoracic), middle (midthoracic), or lower (lower thoracic) esophagus affects staging in some cases. The 8th edition of the AJCC Cancer Staging Manual defines tumor location based on its epicenter as opposed to its proximal border, a departure from previous editions. 

Clinical (cTNM)

Stage 0: Tis N0 M0
Stage I: T1 N0-1 M0
Stage II:
T2 N0-1 M0 or T3 N0 M0
Stage III: T3 N1 M0 or T1-3 N2 M0
Stage IVA:
T4 N0-3 M0 or T1-4b N3 M0
Stage IVB:
M1 

Post-neoadjuvant therapy (ypTNM)

Stage I: T0-2 N0 M0
Stage II: T3 N0 M0
Stage IIIA:
T0-2 N1 M0 
Stage IIIB:
T3 N1 M0 or T0-3 N2 M0 or T4a N0 M0
Stage IVA:
T4a N1-2 M0 or T4b M0 or N3 M0
Stage IVB:
M1 

Pathologic (pTNM)

Stage 0: Tis N0 M0
Stage IA:
T1a N0 M0 G1/X
Stage IB:
T1a N0 M0 G2-3 or T1b N0 M0 G1-3/X or T2 N0 M0 G1 
Stage IIA:
T2 N0 M0 G2-3/X or T3 N0 M0 G1-3 lower or T3 N0 M0 G1 upper/middle
Stage IIB:
T3 N0 M0 G2-3 upper/middle or T3 N0 M0 GX or T1 N1 M0 G1-3/X
Stage IIIA:
T1 N2 M0 G1-3/X or T2 N1 M0 G1-3/X
Stage IIIB:
T2-3 N2 M0 G1-3/X or T3 N1 M0 G1-3/X or T4a N0-1 M0 G1-3/X
Stage IVA:
T4a N2-3 M0 G1-3/X or T4b N0-3 M0 G1-3/X or T1-4b N3 M0 G1-3/X
Stage IVB:
M1 disease 

EAC prognostic stage groups

Clinical (cTNM)

Stage 0: Tis N0 M0
Stage I:
T1 N0 M0
Stage IIA:
T1 N1 M0
Stage IIB:
T2 N0 M0
Stage III:
T2 N1 M0 or T3-4a N0-1 M0
Stage IVA:
T4b N0-3 M0 or T1-4 N2-3 M0
Stage IVB:
M1 

Post-neoadjuvant therapy (ypTNM)

Stage I: T0-2 N0 M0
Stage II:
T3 N0 M0
Stage IIIA:
T0-2 N1 M0 
Stage IIIB:
T3 N1 M0 or T0-3 N2 M0 or T4a N0 M0
Stage IVA:
T4a N1-2 M0 or T4b N0-3 M0 or T1-4b N3 M0
Stage IVB:
M1 

Pathologic (pTNM)

Stage 0: Tis N0 M0
Stage IA:
T1a N0 M0 G1/X
Stage IB:
T1a N0 M0 G2 or T1b N0 M0 G1-2/X
Stage IC:
T1a-b N0 M0 G3 or T2 N0 M0 G1-2
Stage IIA:
T2 N0 M0 G3/X
Stage IIB:
T1 N1 M0 G1-3/X or T3 N0 M0 G1-3/X
Stage IIIA:
T1 N2 M0 G1-3/X or T2 N1 M0 G1-3/X
Stage IIIB:
T2 N2 M0 G1-3/X or T3 N1-2 M0 G1-3/X or T4a N0-1 M0 G1-3/X
Stage IVA:
T4a N2 M0 G1-3/X or T4b N0-3 M0 G1-3/X or T1-4b N3 M0 G1-3/X
Stage IVB:
M1 disease

Prognosis

Overall survival

SEER [2] reports that the 5-year survival rates for esophageal cancer (based on patients diagnosed between 2009 and 2015) are 47% for localized disease, 25% for regional disease, and 5% for distant metastatic disease.

Factors that independently affect prognosis aside from TNM stage include surgical margins (R-status), age, histologic subtype, and tumor size. Low performance status, weight loss, deep tumor ulceration, sinus tract formation, and fistula formation were associated with poor prognosis. Tumor site and grade have not consistently been shown to affect outcomes independently [33].

Recurrence risk

Approximately 38% of patients treated surgically with curative intent experienced recurrence with a median follow-up time of 46 months. The risk of recurrence is projected to surpass 50% by the sixth year. A majority of recurrences occur in the first two years, with recurrence rate tapering from 27/100 in the first year to 4/100 by the sixth year. The failure pattern is predominantly distant -- 72% of those experiencing recurrence have metastases [55].

Treatment

Surgery, radiotherapy, and systemic therapy all have valuable roles in the management of esophageal cancer. Treatment plans should be tailored to the circumstances of each patient and benefit from multidisciplinary consultation and discussion.  

Locoregional Disease

Endoscopic therapy

Endoscopic resection, by either endoscopic mucosal resection or endoscopic submucosal dissection, is the treatment of choice for small (up to 2cm) Tis, T1a, or superficial T1b disease without evidence of nodal metastases, lymphovascular invasion, or grade 3 histology (poor differentiation). Ablation after endoscopic resection can be considered, especially for T1b tumors [38]. These early-stage tumors are rarely associated with nodal metastases, so lymph node dissection may be omitted [56]. Patients with Tis or T1a disease who receive endoscopic resection appear to have similar overall survival outcomes as those who undergo esophagectomy, at considerably less morbidity [57-59]. Endoscopic resection is also appropriate in T1b patients who are unfit for surgery [38]. While the risk of lymph node metastases is substantially higher in this population, outcomes might not necessarily be worse [56, 59].

Surgery alone

Esophagectomy is preferred over endoscopic resection in the definitive management of higher-risk Tis and T1a disease, as well as deeper pT1b lesions (staged after endoscopic resection). It is also recommended for low-risk cT1b and cT2 tumors (<2cm, G1, and N0) [38]. 

Traditionally, the esophagectomy was either transhiatal (laparotomy and cervical anastomosis) or transthoracic (most commonly laparotomy and right thoracotomy but variations exist), with meta-analyses showing similar outcomes [60, 61]. Minimally invasive approaches have gained traction more recently with promising results [62-64]. Regardless of the chosen procedure, adequate lymph node dissection is imperative for accurate staging and independently prognostic for survival [65]. An effort should be made to remove at least 15 nodes, although optimal number is still debated [38, 65]. 

Multimodal therapy

Multimodal therapy is recommended for patients with higher-risk cT1b and cT2 lesions (>2cm or G2+) as well as more locoregionally advanced disease. The preferred treatment for resectable disease is preoperative two-agent chemoradiotherapy followed by esophagectomy, a sequence with demonstrated survival benefit over surgery alone [66].

Patients who are not surgical candidates, including those with cervical esophageal cancer or T4b disease invading the trachea, great vessels, or heart, can be managed with definitive chemoradiotherapy. Two prospective randomized trials suggest that definitive chemoradiotherapy achieve comparable outcomes to preoperative chemoradiotherapy followed by esophagectomy in ESCC, making it tempting to pursue this less morbid treatment for all patients [67, 68]. However, these trials have come under criticism and subsequent retrospective studies found a survival benefit with the addition of surgery [69]. Until further evidence is available, preoperative chemoradiotherapy with esophagectomy remains the standard of care for surgical candidates [38].

There is evidence supporting the use of preoperative or perioperative chemotherapy over surgery alone in EAC, but comparisons to preoperative chemoradiotherapy have been underpowered [70-73]. These strategies are reasonable alternatives in the management of EAC though preoperative chemoradiotherapy is still generally preferred [38].

Metastatic Disease

Chemotherapy and targeted therapies can help manage symptoms and modestly prolong survival. While systemic therapy is associated with higher toxicity, it does not appear to outweigh symptomatic relief as overall quality of life is not diminished [74]. Extrapolating from reports on gastric cancer, the addition of more chemotherapeutic agents can further extend survival and improve response rate, albeit with greater toxicity [75]. Two-agent chemotherapy is considered first line for most patients with esophageal cancer but three-agent chemotherapy may be appropriate in select medically fit patients with good performance status. The combination of a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine) and a platinum agent (e.g., cisplatin or oxaliplatin) is currently considered first line [38].

The addition of targeted therapies to chemotherapy has produced encouraging results in select patient populations [76-78]. Health Canada and the FDA have approved for trastuzumab and ramucirumab for HER2-overexpressing and chemotherapy-refractory patients with GEJ adenocarcinoma, respectively. Other targeted therapies are also showing promising early results, including FDA-approved pembrolizumab for select MSI-H/dMMR EGJ adenocarcinoma [38].

Local Palliative Treatment

Dysphagia and esophageal obstruction are the most common complications of esophageal cancer. Obstruction should be considered as a potential cause for persistent nausea and vomiting. A grading scale is useful to communicate the severity of dysphagia [38]:

Grade 0: Able to tolerate normal diet without special care.
Grade 1: Requires thoroughly-chewed food cut to fragments <18mm in diameter.
Grade 2: Able to swallow only semi-solid food.
Grade 3: Liquid diet only.
Grade 4: Unable to swallow liquids or saliva.

Numerous options are available for the management of severe dysphagia, including stenting (most commonly used), radiation therapy including EBRT and brachytherapy (also commonly used), endoscopic dilation, chemotherapy, and photodynamic therapy. Multimodal treatment is also reasonable [38]. Palliative esophagectomy is generally discouraged due to high morbidity and mortality, especially in view of the poor prognosis of these patients [79]. 

Treatment summary

The above recommendations on the treatment of esophageal cancer are summarized below. A detailed account of options and recommendations is available on the NCCN website [38].

Table 3 Summary of esophageal cancer treatment guidelines

Treatment Morbidity

Surgical morbidity

Esophagectomy is a technically challenging surgery associated with considerable morbidity. While mortality rates have declined to less than 10% owing to advances in surgical technique and perioperative management, medical and surgical complications of esophagectomy occur in up to 75% of patients. Important surgical complications include anastomotic leaks, conduit necrosis, esophageal stricture, recurrent laryngeal nerve paralysis, chylothorax, and cardiopulmonary injury [33]. Postoperatively, patients are also at elevated risk for pneumonia, respiratory distress, reflux, delayed gastric emptying, and dumping syndrome even when the stomach is preserved [80]. It is unclear if complication rates improve with preoperative radiotherapy or chemotherapy [33].

Radiation toxicity

Side effects of esophageal radiation are common and frequently necessitate treatment changes or discontinuation. Concurrent chemotherapy appears to compound toxicity. Among patients treated with radiotherapy in the RTOG 85-01 trial, 25% and 3% experienced acute grade 3 and 4 toxicity, respectively. When chemotherapy was given concurrently, 44% experienced acute grade 3 toxicity and 20% experienced acute grade 4 toxicity. Up to 3% of patients succumbed to chemoradiation-related complications [33]. IMRT has the potential to reduce doses delivered to critical surrounding structures, and a recent meta-analysis suggests that there may be a survival benefit as well [38, 81]. Proton therapy can further reduce radiation to healthy tissue by eliminating the exit dose, though clinical outcomes have not been studied prospectively [38]. Some common and serious complications are below.

Acute toxicities
  1. Esophagitis, occuring in >75% [33]
  2. Dysphagia, occuring in >75% [33]
  3. Nausea +/- vomiting (ondansetron, second line steroids)
  4. Anorexia and malnutrition (nutritional support, enteral feeding as needed)
  5. Dehydration
  6. Fatigue
  7. Cough
  8. Dermatitis
  9. Changes in gastric motility 
  10. Prolonged gastric emptying
  11. Myelosuppression with chemoradiation (follow CBC weekly or more frequently as indicated)
  12. Perforated esophagus

These complications typically resolve within 1-2 weeks of completing therapy but demand close following and aggressive management. 

Subacute and Late toxicities
  1. Esophageal stricture, occuring in >15-20% [33]
  2. Dysphagia
  3. Laryngeal edema
  4. Liver toxicity
  5. Renal toxicity
  6. Cardiac toxicity
  7. Pulmonary toxicity (e.g. radiation pneumonitis, pulmonary fibrosis)

Clinically significant end organ damage is uncommon [33].

Follow up

The value of aggressive surveillance is dependent on the stage and modality of treatment offered. Overall, there is a lack of prospective studies guiding follow up and no expert consensus on what constitutes best practice. One possible schedule is presented below [38]. Surveillance should be tailored to each patient’s unique circumstances.

Tis and T1a treated with endoscopic resection
  1. History and physical every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years. Followed annually afterward.
  2. CBC and chemistry as clinically indicated.
  3. EGD every 3 months for the first year and every 6 months for the second year. Then annually indefinitely.
  4. Imaging as clinically indicated.
  5. Follow nutrition status.
Tis and T1a treated with gastrectomy
  1. History and physical every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years. Followed annually afterward.
  2. CBC and chemistry as clinically indicated.
  3. EGD as clinically indicated. For residual Barrett’s esophagus, EGD surveillance every 3 months for the first year and every 6 months for the second year. Then annually indefinitely.
  4. Imaging as clinically indicated.
  5. Follow nutrition status.
T1bN0 treated with endoscopic resection
  1. History and physical every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years. Followed annually afterward.
  2. CBC and chemistry as clinically indicated.
  3. EGD every 3 months for the first year and every 4-6 months for the second year. Then annually indefinitely. Consider adding EUS to EGD.
  4. Consider CT chest and abdomen with contrast annually for 3 years. As clinically indicated otherwise.
  5. Follow nutrition status.
T1bN0 treated with esophagectomy
  1. History and physical every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years. Followed annually afterward.
  2. CBC and chemistry as clinically indicated.
  3. EGD as clinically indicated. For residual Barrett’s esophagus, EGD surveillance every 3 months for the first year and every 4-6 months for the second year. Then annually indefinitely.
  4. Consider CT chest and abdomen with contrast annually for 3 years. As clinically indicated otherwise.
  5. Follow nutrition status.
T1bN0 treated with definitive chemoradiotherapy
  1. History and physical every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years. Followed annually afterward.
  2. CBC and chemistry as clinically indicated.
  3. EGD every 3-6 months for the 2 years, then annually for another 3 years. Then as clinically indicated.
  4. Consider CT chest and abdomen or PET/CT every 6-9 months for 2 years, then annually for up to 5 years. As clinically indicated otherwise.
  5. Follow nutrition status.
T2+ treated with definitive chemoradiotherapy
  1. History and physical every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years. Followed annually afterward.
  2. CBC and chemistry as clinically indicated.
  3. Consider following CEA and other tumor markers, although value is not known.
  4. EGD every 3-6 months for 2 years, every 3rd month for a third year, and as clinically indicated afterward.
  5. Consider CT chest and abdomen every 6 months for 2 years. As indicated clinically otherwise. 
  6. Follow nutrition status.
T2+ treated with esophagectomy
  1. History and physical every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years. Annually afterward.
  2. CBC and chemistry as clinically indicated.
  3. Consider following CEA and other tumor markers, although value is not known.
  4. EGD only if clinically indicated.
  5. Consider CT chest and abdomen every 6 months for 2 years. As clinically indicated otherwise.
  6. Follow nutrition status.

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